Cyclin-dependent_kinase_inhibitor_1C Knowpia

CDKN1C
Identifiers
Aliases	CDKN1C, BWCR, BWS, KIP2, WBS, p57, p57Kip2, cyclin-dependent kinase inhibitor 1C, cyclin dependent kinase inhibitor 1C
External IDs	OMIM: 600856 HomoloGene: 133549 GeneCards: CDKN1C
Gene location (Human)
Chr.	Chromosome 11 (human)
End	2,885,775 bp
RNA expression pattern
	Top expressed in
	placenta; ; tibial nerve; ; left uterine tube; ; subcutaneous adipose tissue; ; kidney; ; canal of the cervix; ; gastric mucosa; ; fundus; ; myometrium; ; right lung;
	n/a
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	protein binding; cyclin-dependent protein serine/threonine kinase inhibitor activity; protein kinase inhibitor activity; protein-containing complex binding;
Cellular component	cytoplasm; nucleus;
Biological process	positive regulation of transforming growth factor beta receptor signaling pathway; positive regulation of transcription, DNA-templated; regulation of mitotic cell cycle; negative regulation of epithelial cell proliferation; negative regulation of protein serine/threonine kinase activity; cell cycle; negative regulation of transcription, DNA-templated; negative regulation of kinase activity; negative regulation of cyclin-dependent protein kinase activity; negative regulation of phosphorylation; negative regulation of transcription by RNA polymerase II; skeletal system development; kidney development; placenta development; regulation of exit from mitosis; human ageing; myeloid cell differentiation; adrenal gland development; multicellular organism growth; neuron maturation; camera-type eye development; negative regulation of cyclin-dependent protein serine/threonine kinase activity; digestive system development; uterus development; embryonic placenta morphogenesis; genetic imprinting; regulation of lens fiber cell differentiation;
	Sources:Amigo / QuickGO
Orthologs
	1028
	n/a
	ENSG00000273707; ENSG00000129757
	n/a
	P49918
	n/a
	NM_000076; NM_001122630; NM_001122631; NM_001362474; NM_001362475
	n/a
	NP_000067; NP_001116102; NP_001116103; NP_001349403; NP_001349404
	n/a
	Wikidata
View/Edit Human

Cyclin-dependent kinase inhibitor 1C (p57, Kip2), also known as CDKN1C, is a protein which in humans is encoded by the CDKN1C imprinted gene.^[3]

Function edit

Cyclin-dependent kinase inhibitor 1C is a tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations of CDKN1C are implicated in sporadic cancers and Beckwith-Wiedemann syndrome suggesting that it is a tumor suppressor candidate.^[3]

CDKN1C is a tumor suppressor human gene on chromosome 11 (11p15) and belongs to the cip/kip gene family. It encodes a cell cycle inhibitor that binds to G1 cyclin-CDK complexes.^[4] Thus p57KIP2 causes arrest of the cell cycle in G1 phase.

CDKN1C was found to lead to cancer cell dormancy; its gene expression is regulated through the activity of glucocorticoid receptors (GRs) through chromatin remodelling mediated by SWI/SNF.^[5]

Research Methods edit

Since it has been identified that mutation to this tumor suppressing gene can have dramatic effects in a newborn such as macroglossia there has been great research to determine the genetic significance. CDKN1C is prone to error during the process of gene imprinting. The process of gene imprinting is in concert with DNA methylation. This goes makes the gene become transcriptionally silent from the paternal side allowing the maternal gene to be active.^[6] If this gene fails to be properly methylated, or obtains a mutation, there will be a lack of cell cycle suppression leading to the pediatric tumor growth.^[7]

Research methods for this gene have involved different sequencing methods such as Sanger Sequencing. This sequencing method is a three step process that involves PCR, Gel Electrophoresis, and computer analysis to determine DNA sequences.^[8] Sequencing can be helpful in identifying base pair mutations. A study done to assess the phenotypic effects that mutations to this gene will have taken genetic sequencing of a cohort of individuals known to be effected by a mutation on this gene. ^[9] In this study, they found 37 mutations associated with 38 different pedigrees. This went to prove that mutations to the CDKN1C on chromosome 11 would in fact have phenotypic effects on individuals. These effects are further discussed through the different clinical cases that can occur.

Clinical significance edit

A mutation of this gene may lead to loss of control over the cell cycle leading to uncontrolled cellular proliferation. p57KIP2 has been associated with Beckwith-Wiedemann syndrome (BWS) which is characterized by increased risk of tumor formation in childhood.^[10] Loss-of-function mutations in this gene have also been shown associated to the IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies).^[11] Complete hydatidiform moles consist only of paternal DNA, and thus the cells lack p57 expression as the gene is paternally imprinted (silenced). Immunohistochemical stains for p57 can aid with the diagnosis of hydatidiform moles.^[12]

Interactions edit

Cyclin-dependent kinase inhibitor 1C has been shown to interact with:

References edit

^ ^a ^b ^c ENSG00000129757 GRCh38: Ensembl release 89: ENSG00000273707, ENSG00000129757 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2)".
^ Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ (Mar 1995). "p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene". Genes & Development. 9 (6): 650–62. doi:10.1101/gad.9.6.650. PMID 7729684.
^ Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B (July 2021). "Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer". Nature Communications. 12 (1): 4360. Bibcode:2021NatCo..12.4360P. doi:10.1038/s41467-021-24537-3. PMC 8285479. PMID 34272384.
^ Amacher S. "Epigenetics Impriting" (PDF). University of California Berkeley.
^ Cedar H, Bergman Y (May 2009). "Linking DNA methylation and histone modification: patterns and paradigms". Nature Reviews. Genetics. 10 (5): 295–304. doi:10.1038/nrg2540. PMID 19308066. S2CID 5450674.
^ "Sanger Sequencing Steps & Method". Merck KGaA. Darmstadt, Germany.
^ Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, et al. (September 2015). "Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization". Human Mutation. 36 (9): 894–902. doi:10.1002/humu.22824. PMID 26077438. S2CID 37398295.
^ Hatada I, Nabetani A, Morisaki H, Xin Z, Ohishi S, Tonoki H, Niikawa N, Inoue M, Komoto Y, Okada A, Steichen E, Ohashi H, Fukushima Y, Nakayama M, Mukai T (Oct 1997). "New p57KIP2 mutations in Beckwith-Wiedemann syndrome". Human Genetics. 100 (5–6): 681–3. doi:10.1007/s004390050573. PMID 9341892. S2CID 21120202.
^ Riccio A, Cubellis MV (Jul 2012). "Gain of function in CDKN1C". Nature Genetics. 44 (7): 737–8. doi:10.1038/ng.2336. PMID 22735584. S2CID 205345787.
^ LeGallo RD, Stelow EB, Ramirez NC, Atkins KA (May 2008). "Diagnosis of hydatidiform moles using p57 immunohistochemistry and HER2 fluorescent in situ hybridization". American Journal of Clinical Pathology. 129 (5): 749–755. doi:10.1309/7XRL378C22W7APBT. PMID 18426735.
^ Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N (Dec 2003). "p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus". The Journal of Biological Chemistry. 278 (52): 52919–23. doi:10.1074/jbc.M309334200. PMID 14530263.
^ Joaquin M, Watson RJ (Nov 2003). "The cell cycle-regulated B-Myb transcription factor overcomes cyclin-dependent kinase inhibitory activity of p57(KIP2) by interacting with its cyclin-binding domain". The Journal of Biological Chemistry. 278 (45): 44255–64. doi:10.1074/jbc.M308953200. PMID 12947099.
^ Reynaud EG, Leibovitch MP, Tintignac LA, Pelpel K, Guillier M, Leibovitch SA (Jun 2000). "Stabilization of MyoD by direct binding to p57(Kip2)". The Journal of Biological Chemistry. 275 (25): 18767–76. doi:10.1074/jbc.M907412199. PMID 10764802.
^ Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y (Feb 1998). "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1392–7. Bibcode:1998PNAS...95.1392W. doi:10.1073/pnas.95.4.1392. PMC 19016. PMID 9465025.

External links edit

GeneReviews/NIH/NCBI/UW entry on Beckwith-Wiedemann Syndrome
CDKN1C human gene location in the UCSC Genome Browser.
CDKN1C human gene details in the UCSC Genome Browser.

[refGRCh38Ensembl-1] ENSG00000129757 GRCh38: Ensembl release 89: ENSG00000273707, ENSG00000129757 – Ensembl, May 2017

[2] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-3] "Entrez Gene: CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2)".

[pmid7729684-4] Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ (Mar 1995). "p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene". Genes & Development. 9 (6): 650–62. doi:10.1101/gad.9.6.650. PMID 7729684.

[5] Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B (July 2021). "Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer". Nature Communications. 12 (1): 4360. Bibcode:2021NatCo..12.4360P. doi:10.1038/s41467-021-24537-3. PMC 8285479. PMID 34272384.

[6] Amacher S. "Epigenetics Impriting" (PDF). University of California Berkeley.

[pmid19308066-7] Cedar H, Bergman Y (May 2009). "Linking DNA methylation and histone modification: patterns and paradigms". Nature Reviews. Genetics. 10 (5): 295–304. doi:10.1038/nrg2540. PMID 19308066. S2CID 5450674.

[8] "Sanger Sequencing Steps & Method". Merck KGaA. Darmstadt, Germany.

[pmid26077438-9] Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, et al. (September 2015). "Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization". Human Mutation. 36 (9): 894–902. doi:10.1002/humu.22824. PMID 26077438. S2CID 37398295.

[pmid-10] Hatada I, Nabetani A, Morisaki H, Xin Z, Ohishi S, Tonoki H, Niikawa N, Inoue M, Komoto Y, Okada A, Steichen E, Ohashi H, Fukushima Y, Nakayama M, Mukai T (Oct 1997). "New p57KIP2 mutations in Beckwith-Wiedemann syndrome". Human Genetics. 100 (5–6): 681–3. doi:10.1007/s004390050573. PMID 9341892. S2CID 21120202.

[doi.10.1038/ng.2336-11] Riccio A, Cubellis MV (Jul 2012). "Gain of function in CDKN1C". Nature Genetics. 44 (7): 737–8. doi:10.1038/ng.2336. PMID 22735584. S2CID 205345787.

[12] LeGallo RD, Stelow EB, Ramirez NC, Atkins KA (May 2008). "Diagnosis of hydatidiform moles using p57 immunohistochemistry and HER2 fluorescent in situ hybridization". American Journal of Clinical Pathology. 129 (5): 749–755. doi:10.1309/7XRL378C22W7APBT. PMID 18426735.

[pmid14530263-13] Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N (Dec 2003). "p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus". The Journal of Biological Chemistry. 278 (52): 52919–23. doi:10.1074/jbc.M309334200. PMID 14530263.

[pmid12947099-14] Joaquin M, Watson RJ (Nov 2003). "The cell cycle-regulated B-Myb transcription factor overcomes cyclin-dependent kinase inhibitory activity of p57(KIP2) by interacting with its cyclin-binding domain". The Journal of Biological Chemistry. 278 (45): 44255–64. doi:10.1074/jbc.M308953200. PMID 12947099.

[pmid10764802-15] Reynaud EG, Leibovitch MP, Tintignac LA, Pelpel K, Guillier M, Leibovitch SA (Jun 2000). "Stabilization of MyoD by direct binding to p57(Kip2)". The Journal of Biological Chemistry. 275 (25): 18767–76. doi:10.1074/jbc.M907412199. PMID 10764802.

[pmid9465025-16] Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y (Feb 1998). "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1392–7. Bibcode:1998PNAS...95.1392W. doi:10.1073/pnas.95.4.1392. PMC 19016. PMID 9465025.

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